1. Technical Field
This invention relates to the classification of individuals by features related to tissue properties. More particularly, the invention relates to methods of characterizing the tissue by features related to the absorbance spectrum of fat in adipose tissue, based on near-IR spectral measurements.
2. Discussion of the Prior Art
Near-infrared (NIR) tissue spectroscopy is a promising noninvasive technology that bases measurements on the irradiation of a tissue site with NIR energy in the 700-2500 nm wavelength range. The energy is focused onto an area of the skin and propagates according to the scattering and absorbance properties of the skin tissue. Thus, energy that is reflected by the skin or that is transmitted through the skin and is detected provides information about the tissue volume encountered. Specifically, the attenuation of the light energy at each wavelength is a function of the structural properties and chemical composition of the tissue. Tissue layers, each containing a unique heterogeneous particulate distribution, affect light absorbance through scattering. Chemical components such as water, protein, fat and blood analytes absorb light proportionally to their molar concentration through unique absorbance profiles or signatures. The measurement of tissue properties, characteristics or composition is based on the technique of detecting the magnitude of light attenuation resulting from its respective scattering and/or absorbance properties.
While noninvasive prediction of blood analytes, such as blood glucose concentration, has been pursued through NIR spectroscopy, the reported success and product viability has been limited by the lack of a system for compensating for variations between individuals that produce dramatic changes in the optical properties of the tissue sample. For example, see O. Khalil Spectroscopic and clinical aspects of non-invasive glucose measurements, Clin Chem; vol. 45: pp. 165-77 (1999); or J. Roe, B. Smoller, Bloodless Glucose Measurements, Critical Reviews in Therapeutic Drug Carrier Systems, vol. 15, no. 3, pp. 199-241, (1998). These variations are related to structural differences in the irradiated tissue sample between individuals and include, for example, the thickness of the dermis, distribution and density of skin collagen and percent body fat. While the absorbance features caused by structural variation are repeatable by subject, over a population of subjects they produce confounding nonlinear spectral variation. See C. Tan, B. Statham, R. Marks and P. Payne. Skin thickness measurement by pulsed ultrasound: its reproducibility, validation and variability, British Journal of Dermatology, vol. 106, pp. 657-667, (1982). Also see S. Shuster, M. Black, E. McVitie, The influence of age and sex on skin thickness, skin collagen and density British Journal of Dermatology, vol. 93, (1975). See also J. Durnin, M. Rahaman, The assessment of the amount of fat in the human body from measurements of skin fold thickness, British Journal of Nutrition, vol. 21, (1967).
Additionally, variations in the subject""s physiological state affect the optical properties of tissue layers and compartments over a relatively short period of time. Such variations, for example, may be related to hydration levels, changes in the volume fraction of blood in the tissue, hormonal stimulation, temperature fluctuations and blood hemoglobin levels.
While these structural and state variations are the largest sources of variation in the measured near-infrared absorbance spectra, they are not indicative of blood analyte concentrations. Instead they cause significant nonlinear spectral variation that limits the noninvasive measurement of blood analytes through optically based methods. For example, several reported methods of noninvasive glucose measurement develop calibration models that are specific to an individual over a short period of time. See, K. Hazen, Glucose determination in biological matrices using near-infrared spectroscopy, Doctoral Dissertation, University of Iowa, (August 1995). Also see M. Robinson, R. Eaton, D. Haaland, G. Koepp, E. Thomas, B. Stallard and P. Robinson, Noninvasive glucose monitoring in diabetic patients: a preliminary evaluation, Clin. Chem, vol. 38/9, pp. 1618-1622, (1992). Also see S. Malin, T. Ruchti, T. Blank, S. Thennadil and S. Monfre, Noninvasive prediction of glucose by near-infrared diffuse reflectance spectroscopy, Clin. Chem, vol. 45:9, pp.1651-1658, (1999).
A related application, S. Malin, T. Ruchti, An Intelligent System For Noninvasive Blood Analyte Prediction, U.S. patent application Ser. No 09/359,191; filed Jul. 22, 1999, disclosed an apparatus and procedure for substantially reducing this problem, by classifying subjects according to spectral features that are related to the tissue characteristics prior to blood analyte prediction. The extracted features are representative of the actual tissue volume irradiated. The groups or classes are defined on the basis of tissue similarity such that the spectral variation within a class is small compared to the variation between classes. These internally consistent classes are more suitable for multivariate analysis of blood analytes since the largest source of spectral interference is substantially reduced. In this manner, by grouping individuals according to the similarity of spectral characteristics that represents the tissue state and structure, the confounding nonlinear variation described above is reduced and prediction of blood analytes is made more accurate.
The general method of classification relies on the determination of spectral features most indicative of the sampled tissue volume. The magnitude of such features represents an underlying variable, such as the thickness of tissue or level of hydration.
The absorbance of light by adipose tissue in the sub-dermis, consisting primarily of cells rich in triglycerides, a class of fatty substance, is among the most significant source of spectral variation in noninvasive near-infrared measurements. While adipose tissue profoundly influences the overall measurement, the volume fraction of fluid rich in blood analytes is relatively small compared to that present in other layers of the skin.
The dermis, for example, is richly supplied with a vascular network. At the interface between the dermis and subcutaneous fat is the deep vascular plexus, a collection of vessels that runs parallel to the skin surface. From the deep vascular plexus, blood vessels rise toward the skin surface to another dense parallel collection of vessels called the superficial vascular plexus, located 0.3 mm to 0.6 mm from the skin surface.
Consequently, the capillary beds of the dermis are targeted for irradiation and measurement of blood analytes, since they have a high volume fraction of analytes, such as glucose, that vary in accordance with actual blood concentration, compared to other layers of the skin. On the other hand, the absorbance of light by the constituents of adipose tissue contributes only confounding effects to the measurement of the targeted analyte, yet it represents, second only to the absorbance of water, the largest source of spectral variation. For example, FIG. 1 shows a near-infrared absorbance spectrum measured on a human subject with large absorbance bands 101, 102, 103, marked by arrows, due to fat stored in adipose tissue. The relative absorbance due to the presence of a typical blood analyte in the sampled tissue volume, such as glucose, is approximately three orders of magnitude smaller than the designated fat absorbance bands.
Thus, the absorbance of light by adipose tissue creates two major obstacles to accurate blood analyte determination. First, the total absorbance related to adipose tissue is a large interference and is not indicative of blood analyte concentrations. Compounding this interference is the fact that the varied attenuation of light by adipose tissue is difficult to model due to the complex nature of the diffusely reflected light in layered systems. Second, the measured absorbance of fat by adipose tissue changes in a manner related to the optical properties of the preceding tissue layers, namely, the dermis, epidermis and stratum corneum. For a given light intensity level, the absorbance due to fat in adipose tissue tends to be constant. However, the light incident on the adipose tissue varies as the surrounding tissue changes according to its physiological state. Thus, the magnitude of fat absorbance in the tissue volume sampled is indirectly related to these changes due to physiological state fluctuations.
Therefore, features related to the absorbance of fat in adipose tissue can be used to classify the nature of the tissue volume sampled with a near-infrared measurement device. The classification of subjects according to the similarity of such features leads to a greater homogeneity of the sampled tissue volume and a reduction in interference related to the skin tissue. This inevitably produces a superior measurement of the concentration of biological compounds in skin, such as blood analytes, among the sub-groups.
Body composition is an important indicator of health status, and body composition determination plays an important role in health risk assessment and diagnosis, and in monitoring of physical training programs. (See. V. Heyward, L. Stolarczyk, Applied Body Composition Assessment, Champaign, Ill.: Human Kinetics, (1996)). Obesity, for example, is a serious health problem that reduces life expectancy by increasing one""s risk of developing coronary artery disease, hypertension, Type II diabetes, obstructive pulmonary disease, osteoarthritis and certain types of cancer. The increased health risks associated with obesity are related to the total amount of body fat. Not surprisingly, a large number of methods for estimating body composition exist, many of them based on indirect measurements; for example, hydrostatic weighing, bioelectrical impedance, skin fold measurements and others (See V. Heyward, L. Stolarczyk, Applied Body Composition Assessment, Champaign, Ill.: Human Kinetics, (1996)). In addition, near-infrared analysis in the wavelength range 700-1100 nm has been applied to the noninvasive measurement of body fat (See J. Conway, K. Norris, C. Bodwell, A new approach for the estimation of body composition: infrared interactance, The American Journal of Clinical Nutrition, pp. 1123-1130, (December 1985).
R. D. Rosenthal in Near infrared apparatus and method for determining percent fat in a body, U.S. Pat. No. 4,850,365, issued Jul. 25, 1989 and again in Near-infrared apparatus and method for determining percent fat in a body, U.S. Pat. No. 4,928,014 issued May 22, 1990; and A. Roper and K. Johnson, in Method and apparatus for measuring thickness of fat using infrared light, U.S. Pat. No. 5,014,713, issued May 14, 1991, disclose methods of performing near-infrared analysis in the 700-1100 nm wavelength regions for the purpose of body composition analysis including the determination of the percent fat and the thickness of fat.
The use of near-infrared analysis has the advantage of being strictly noninvasive, convenient and affordable. The reported methods are similar and generally involve the irradiation of the tissue with near-infrared light at several wavelengths in the 740-1100 nm range and detecting the light absorbed at a multiplicity of wavelengths. A model is constructed for predicting the percent body fat or the thickness of the subcutaneous fat layer on the basis of the measurement, given reference values from an alternate technique of body composition assessment. Conway, for example, used the second derivative of the absorbance spectrum at 916 nm and 1026 nm to estimate the percent fat of several individuals.
Rosenthal reports two similar methods for determining percent fat in a body through the use of the measured absorbance at one wavelength and one bandwidth, respectively, and a mathematical model relating the percent body fat to the absorbance measurement. In addition, data on a plurality of physical parameters of the body, such as height, weight, exercise level, sex, race, waste-to-hip measurement and arm circumference, are proposed for use along with the measured near-infrared absorbance in the quantitative determine of body fat content.
Roper et al. determine the fat thickness in the body through a measuring device involving a pair of infrared emitting diodes and a detector array. A variety of wavelengths in the 700-1100 nm range are detected by the array and produce signals proportional to the light intensity transmitted from the body. These signals are summed and amplified forming a composite signal. The amplitude of this composite signal is claimed to be indicative of the thickness of the layer of fat.
While the reported methods of near-infrared analysis offer some advantage, their utility is significantly compromised due to the wavelength region selected for analysis. It is well understood that melanin is a significant absorber of light below 1100 nm (See R. Anderson, J. Parrish, The optics of human skin, J. of Investigative Dermatology, vol. 77 (1), pp. 13-19, (1981). Therefore, skin color causes large spectral variation at wavelengths below 1100 nm and represents a major confounding effect and source of bias. Furthermore, the depth of penetration in this wavelength region far exceeds the depth of subcutaneously stored fat. In addition, the potential interference due to visible light in this wavelength region is well known and requires special measurement equipment and requirements for blocking it. A method for determining the thickness of subcutaneous fat and percent body fat through the use of near-infrared energy at higher wavelengths (1100-2500) nm would clearly be advantageous. In this range the depth of penetration is limited to subcutaneous tissue. The optical properties of the adipose cells, as manifested in the measured absorbance spectrum, can be used to estimate the thickness of the subcutaneous tissue and overall level of fatness of the individual.
The invention provides a novel apparatus and related procedures for determination of features related to the absorbance of fat in adipose tissue and subsequent classification of subjects prior to blood analyte estimation. A method is provided for determining the thickness of subcutaneous fat and percent body fat through the use of near-infrared energy at longer wavelengths in the spectral region of 1100-2500 nm. In this range the depth of penetration is limited to subcutaneous tissue. The optical properties of the adipose cells, as manifested in the measured absorbance spectrum, can be used to estimate the thickness of the subcutaneous tissue and overall level of fatness of the individual without interference from deeper tissue layers or skin pigmentation.
In general, the apparatus includes an energy source, a wavelength separator, an optical interface to the subject, a sensor element, and an analyzer. The general method of the invention includes the steps of measuring the NIR absorbance spectra of an in vivo tissue sample; detecting outliers, invalid measurements related to various sources of error; subjecting the measured spectrum to various pre-processing techniques; feature extraction, in which the spectral features specifically related to absorbance of fat in adipose tissue are identified and isolated; and calibration, in which the extracted features are compared to a calibration set of exemplary measurements to characterize the spectrum for further blood analyte prediction. A skin fold thickness estimate may be made, and a subsequent estimate of percent body fat.